Chlorpromazine (CPZ) and 10 of its metabolites have been monitored simultaneously in relatively crude extracts from various biological materials, using a novel form of reverse search GC/MS. The feasibility of generating analogous "metabolite profiles" for other major antipsychotic drugs has also recently been established in preliminary studies at our laboratory. It is now proposed to refine the provisional CPZ GC/MS/COM methodology, to expand the number of metabolites being monitored, and to apply the resulting assay to a statistically significant number of patients including drug responders and nonresponders during the initial and chronic phases of therapy. By correlating trends in the relative concentrations of a large number of major CPZ metabolites with the clinical status of patients, it is anticipated that inter-patient differences in metabolic pathways will be observed. From these it is hoped that criteria by which responders can be distinguished from nonresponders can be established. Conventional GC/MS procedures will be used to attempt to identify presently uncharacterized metabolites in various fatty, gelatinous, and keratinous biological matrices (e.g. brain, eyes, skin, etc.) in which CPZ is known to accumulate. Following establishment of a final CPZ metabolite panel, our existing multimetabolite assays for thioridazine and mesoridazine will be similarly refined and applied in the same manner to appropriate patients. Subsequently, time permitting, corresponding provisional methodology for low-dosage phenothiazines, such as fuphenazine, and for haloperidol, the most widely used butyrophenone, will be generated.